The field of the invention relates to vitamin D compounds, and more particularly to (22E)-2-methylene-22-dehydro-1α,24,25-trihydroxy-19-nor-vitamin D3 analogs and their pharmaceutical uses.
The natural hormone, 1α,25-dihydroxyvitamin D3 and its analog in the ergosterol series, i.e., 1α,25-dihydroxyvitamin D2, are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established. (See Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987)). Many structural analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side-chain homologated analogs, and fluorinated analogs. Some of these vitamin D analogs exhibit biological activities that differ from the biological activities of the native vitamin D compounds, including decreased or increased biological activity related to calcium regulation and cell differentiation as compared to the native vitamin D compounds. The difference in biological activities exhibited by vitamin D analogs may be exploited in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies, where some of the biological activities of vitamin D compounds are desirable, but other of the biological activities of vitamin D compounds are not desirable.
One class of vitamin D analogs, i.e., the so called 19-nor-vitamin D compounds, is characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Several 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) exhibit a selective, biological activity profile characterized by a high potency in inducing cellular differentiation, and a low potency in inducing calcium-mobilizing activity. Thus, some of these compounds are potentially useful as therapeutic agents for the treatment of malignancies or the treatment of various skin disorders. Methods for synthesizing such 19-nor-vitamin D analogs have been described. (See Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
Vitamin D3 analogs substituted at carbon 2 (C-2) also have been synthesized, including compounds substituted at C-2 with: hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713); 2-alkyl groups (DeLuca et al., U.S. Pat. No. 5,945,410); and 2-alkylidene groups (DeLuca et al., U.S. Pat. No. 5,843,928). Like the 19-nor analogs, these compounds also exhibit selective, biological activity profiles. In particular, U.S. Pat. No. 5,843,928 discloses a 2-methylene-(20S)-1α,25-dihydroxy-19-nor-vitamin D3 analog otherwise referred to as “2MD.” Studies of these analogs indicate that binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
Additional vitamin D analogs have been synthesized and tested, including analogs which are characterized by the presence of a methylene substituent at carbon 2 (C-2), a hydroxyl group at both carbon 1 (C-1) and carbon 3 (C-3), and a shortened side chain attached to carbon 20 (C-20). (See DeLuca et al., U.S. Pat. No. 6,566,352, disclosing 1α-hydroxy-2-methylene-19-nor-pregnacalciferol; DeLuca et al., U.S. Pat. No. 6,579,861, disclosing 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol; and DeLuca et al., U.S. Pat. No. 6,627,622, disclosing 1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol). These analogs exhibit a relatively high binding activity to vitamin D receptors and a relatively high cell differentiation activity, but little if any calcemic activity as compared to 1α,25-dihydroxyvitamin D3. The biological activities of these analogs make them excellent candidates for a variety of pharmaceutical uses.
Vitamin D analogs having 17-ene double bonds as well as vitamin D compounds having a double bond in the side chain also are known and have been proposed for various pharmacological uses. (See Bretting, U.S. Pat. No. 5,545,633; Mourino et al., U.S. Pat. No. 5,929,056; and von Daehne, et al., U.S. Pat. No. 6,399,797). Bone diseases such as osteoporosis, skin disorders such as psoriasis, cancers such as leukemia, and cosmetic conditions such as wrinkles are just some of the applications proposed for such compounds. 2-alkylidene compounds having a side chain with a double bond therein also have been described (See DeLuca et al., U.S. Pat. No. 5,843,928).
Although a large number of vitamin D analogs exist, new analogs that may be utilized in therapeutic methods are desirable. Here, the inventors describe further vitamin D analogs.